Our Program Project is designed to improve the outcome of organ transplantation. Its main focus is upon improving methods for the control of transplant rejection and certain complications of immunosuppression. In patients we will build upon our original studies in which monoclonal antibodies to T lymphocytes have been shown to control acute rejection reactions very successfully. Newer antibodies, including "hybrid" monoclonals bearing a constant region of human origin and variable regions of murine origin will be tested. Other antibodies will soon be ready for clinical trial. Several approaches to more refined testing of the immune status of transplant recipients will also be evaluated. In order to develop new approaches to the use of highly selective monoclonal antibodies against particular cells which are activated to participate in transplant rejection basic projects involving genetically defined mice and pre-clinical trials in monkeys (cynomolgus) are planned. Mouse experiments are essential for the determination of mechanisms of action of selected monoclonals for immunosuppression and monkey experiments are of value in the pre-clinical testing of antibodies which are directed to antigens on human cells but cross react with the cells of certain other primates. New monoclonals will be prepared using target cells from several sources, including cells from rejecting organs, which can be grown from graft biopsies and cloned. Special attention will also be paid to the elucidation of the importance of histocompatibility antigen systems which are more widely shared in mammalian populations, the "public antigens" which may be of great importance in transplant rejection. These studies will make use both of human cells and of cells from mice. In other experiments further exploration of the biology of cytomegalovirus infections in mice will be carried out. These studies will include an evaluation of the importance of major histocompatibility antigen restriction in vivo to the clearance of infecting viruses as well as new strategies for the treatment or avoidance of infection which may be applicable in clinical management.